The overall goal of this collaborative project is to develop CDK5 as a therapeutic target in pancreatic cancer. This project is based on our preliminary data, showing that CDK5 inhibition in pancreatic cancer cell lines reduced their migration and invasion in vitro, and their tumor growth and metastasis in vivo. In addition, we have found that inhibition of CDK5 in pancreatic cancer cells inhibits signal transduction pathways that are activated by ras. This suggests that CDK5 inhibition may antagonize the ras pathway in pancreatic cancer. Since ras mutation or dysregulation is present in the vast majority of pancreatic adenocarcinomas, this is a possibility of considerable potential therapeutic significance. A genetically engineered animal model for the role of CDK5 in pancreatic tumorigenesis and metastasis will be developed, based on pancreas specific ablation of the Cdk5 gene in the well characterized Pdx1-cre K-ras?G12D p53?R172H model of pancreatic cancer (Hingorani et al, 2005). The effect of CDK5 inhibition on downstream ras-mediated signaling pathways in pancreatic cancer cells, including RalA, RalB, MEK/ERK, PI3-K and Hedgehog, will be examined. The potential that CDK5 affects oncogenic signal transduction through a linear pathway from RalA, through effectors src and STAT3, will be explored. The potential that blocking these CDK5-mediated pathways may induce sensitivity to chemotherapeutic agents will be examined. The ability of CDK5 to induce or augment aspects of neoplastic transformation in pancreatic epithelial cells will be investigated. A selective CDK5 inhibitor will be evaluated for its potential therapeutic efficacy in an in vivo preclinical platform of human pancreatic adenocarcinoma. The effect of combination therapy, using this CDK5 inhibitor with standard gemcitabine or other chemotherapeutic agents, will be explored. PUBLIC HEALTH RELEVANCE: Our preliminary data indicate that inhibition of CDK5 can limit growth and metastasis of pancreatic cancer. In the current project, we will develop CDK5 as a potential therapeutic target for the control of pancreatic cancer.